The chemical and biological literature abounds with reports on the benzo[de]isoquinoline-1,3-diones (I) due in great part to their cytotoxic and antitumor activities (Proc. 10th. Int. Congress of Chemother., 1977;2:1216; Cancer Chemother. Pharmac., 1980;4:61; Eur. J. Med. Chem., 1981;16:207). Paul, et al. (Arzneim Forsch/Drug Res., 1984;34:1243) performed a retrospective analysis of hundreds of compounds within the benzo[de]isoquinolone-1,3-dione class, and showed that all of their cytotoxic/antitumor biological activity was associated with the presence of an extended amino containing alkyl group at the diimide nitrogen (R.sub.2). ##STR2##
Longer chains or substituted chains were also tolerated. The cytotoxic/antitumor activities of these agents are mediated by their binding to DNA (Biochem., 1982;21:2070;J. Med. Chem., 1996;39:1609). A number of clinical candidates have been studied for the treatment of tumors and leukemia such as mitonafide (II), amonafide (III), and DMP840 (IV) (Cancer Res., 1994;54:159;Proc. Nat. Acad. Sci., 1995;92:8950). ##STR3##
As cytotoxic and antitumor agents, compounds such as II-IV also display antibacterial activity (Chatterjee, et al., Proc. Nat. Acad. Sci., 1995;92:8950) and antiparasitic activity (Antimicrob. Agents Chemother., 1996;40:706). Because they bind DNA, they are able to inhibit mammalian and bacterial topoisomerases mediating the ultimate death of the cells (Antimicrob. Agents Chemother., 1996;40:706). As antibacterial agents, these compounds lack specificity and are overly toxic to mammalian cells.
Due to the ever increasing incidence of antibiotic resistance appearing around the world, new antibacterials of novel structure have become very important for the treatment of bacterial infections (J. Med. Chem., 1996;39:3853).
The subject of this invention is the discovery that the antibacterial activity of the benzo[de]isoquinoline-1,3-diones can be effectively separated from the cytotoxic and antitumor activities by the replacement of the alkyl amino group in compounds I-IV with a hydroxyl group (I, R.sub.2.dbd.OH). These 2-hydroxy benzo[de]isoquinoline-1,3-diones (V) do not strongly intercalate or bind DNA, and in fact, are selective inhibitors of bacterial DNA gyrase and DNA topoisomerase IV. Compounds that inhibit two bacterial targets are expected to offer significant advantages in treatment of bacterial infection by lowering the frequency of bacterial resistance (Cozzarelli, et al., Proc. Natl. Acad. Sci. USA, 1995;92:11801; Hosino, et al., Antimicrobial Agents Chemother., 1994;38:2623). ##STR4##
Certain compounds of the type V have been described in U.S. Pat. No. 5,076,831 as intermediates to Va and as additives in the preparation of herbicidal formulations.
Compounds of type V were reported as synthetic intermediates leading to ring contracted product (J. Med. Chem., 1992;35:663;Zh. Org. Chim., 1977;13:2194). Studies of the base hydrolysis of compounds of type V have also been described (Zh. Org. Chim., 1973;9:171 and 1970;6:1480) X-ray studies of compounds V were reported (Zh. Strukt. Khim., 1970;11:939) as well as acylations of the hydroxy group (Zh. Org. Chim., 1972;8:165).
German patent DE2417789 and U.S. Pat. No. 3,941,791 describes compounds of the Type V as dyes and brighteners. U.S. Pat. No. 4,007,192 refers to a process of preparing the 6,7-dicarboxylic acids of compound V. U.S. Pat. No. 3,880,859 reports a wide variety of O-alkyl analog (Va) as fiber whiteners. There were no claims or disclosures of any antibacterial activity in any of the references cited above.